The present invention primarily relates to new uses for the prophylaxis and/or treatment of inflammation, namely compounds of the formula (X)
salts of compounds of the formula (X) and mixtures containing or consisting of two or more different compounds of the formula (X), two or more different salts of compounds of the formula (X) or one or more different compounds of the formula (X) and one or more different salts of compounds of the formula (X), wherein for R1, R2 and R3 that herein described, in particular that stated in the claims, applies, for use in a method for the prophylaxis and/or treatment of inflammation, in particular of inflammation of the skin, in particular in a method for reducing the release of TNF-alpha, and/or for reducing the release of an interleukin, preferably of IL-1, IL-6 and/or IL-8, and/or for reducing the release of a prostaglandin, preferably of PGE2, and/or for reducing the release of interferon-gamma and/or NF-κB.
The present invention also relates to preparations, in particular to preparations used for nutrition or enjoyment, pharmaceutical preparations, cosmetic preparations and dermatological preparations, which contain a compound to be used according to the invention, a salt to be used according to the invention or a mixture (as described herein) to be used according to the invention, for use in a method for the prophylaxis and/or treatment of inflammation, in particular of inflammation of the skin, in particular in a method for reducing the release of TNF-alpha, and/or for reducing the release of an interleukin, preferably of IL-1, IL-6 and/or IL-8, and/or for reducing the release of a prostaglandin, preferably of PGE2, and/or for reducing the release of interferon-gamma and/or NF-κB.
Further aspects of the present invention follow from the following description.
There is a constant need to provide inflammation-inhibiting substances for the protection of cells or tissues (of people and animals), in particular of the skin, above all for use in cosmetic preparations, pharmaceutical preparations, foodstuffs or semi-luxury products. In particular there is a constant need to find new substances with anti-inflammatory activity, which support the natural defence mechanisms against inflammation in physiological systems (of people and animals). In this respect, there is particularly great interest in substances from natural extracts. Particularly attractive for use in foods are plants or parts or extracts of plants, which have a long history of edible consumption.
In the context of the present text, the term “skin” comprises not only the (human or animal) skin in the usual sense, but rather cell layers in general which cover internal and/or external surfaces on/in the human or animal body. Accordingly, in the context of the present text, the term “skin” comprises surface and glandular epithelia, i.e. in particular also mucous membranes, e.g. the oral mucosa, the gastric mucosa and the intestinal mucosa. As barrier organs of the (human) body, the mucous membranes are exposed to external influences to a particular extent. They line the various body cavities which are either in contact with the external environment (e.g. mouth and throat) or the internal organs of a body (e.g. intestinal lumen).
Many intrinsic factors (e.g. genetic predisposition) and extrinsic factors (e.g. damage to the skin barrier, influence of UV light, skin-irritant or allergy-triggering substances) can lead to skin irritation or dysfunctions of the skin.
In the context of the present text “skin irritation” is understood to mean any change in the skin, which triggers indisposition (“sensorial malaise”), and/or is characterized by symptoms of dry, reddened and/or inflamed skin. The term “sensorial malaise” also includes states which are associated with pruritus or pains.
Skin irritation can include the following skin conditions: sensitive skin, for example sensitive scalp, easily damaged skin, atopic skin (atopy) and irritated or inflamed skin, which can appear in the form of skin reddening (erythema).
Skin irritation can in particular also concern or comprise                irritation of the mucous membranes in the oral cavity, for example periodontitis and gingivitis (as described in detail below),        irritation and infections of the airways (as described in detail below; see also US 2009/0238905 on this), for example rhinosinusitis (common cold), sinusitis and pharyngitis/tonsillitis, and        irritation of the gastrointestinal tract (as described in detail below; see also US 2009/0238905 on this).        
The problem of sensitive skin affects a growing number of adults and children. It is believed that a proportion of up to 50% of the population have sensitive skin (L. Misery et al., Ann. Dermatol. Venereol. 2005, 132, 425-429). Sensitive skin describes skin which has a decreased threshold for irritant substances, and also hyper-reactive, intolerant and also atopic skin. In the case of people with sensitive or easily damaged skin, the so-called “stinging” (Engl. “to sting”=burn, stab, be painful) can be observed. Typical symptoms which are associated with “stinging” or “sensitive skin” in general are skin reddening, tingling, feelings of tension and burning of the skin and pruritus. They can be triggered by certain ambient influences, e.g. massage, influence of surfactants, weather (heat, cold, dryness or high atmospheric humidity), thermal or UV radiation (e.g. emanating from the sun) or even by psychological stress.
Sensitive scalp is also characterized by skin reddening, tingling, burning and stinging. Triggers are for example soap, shampoos or other hair care products, surfactants, water with a high calcium carbonate content and/or (mechanical) stress. Erythema and hyperseborrhoea (excessive sebaceous secretion) of the scalp and dandruff are often accompanied by the said symptoms.
Atopy (atopic syndrome) is observed (with a rising trend) in ca. 10-20% of the population in industrialized countries. This is a hypersensitivity of the skin to substances from the environment with an increased tendency to development of hypersensitivity reactions of the immediate type (allergies) towards substances from the natural environment. It is believed that atopy has genetic causes. Atopy can appear as atopic dermatitis. In this case, the skin barrier is damaged, and the skin is often inflamed and itches.
Periodontitis (as an example of an inflammatory reaction of the gums or the oral mucosa) is an inflammation of the periodontium (dental periosteum), i.e. the tissue which surrounds and supports the teeth. The periodontium consists of various tissues: gingival epithelium (gingiva; gum), connective tissue of the gingiva, dental periosteum (periodontium, desmodontium), dental cement and surrounding alveolar bone. The dental periosteum lies between the surface of the root and the alveolar bone and is a cell-rich connective tissue which holds the teeth in the osseous tooth socket, the alveolus. 53 to 74% of the periodontal gap consists of collagen and oxytalan fibre bundles. Periodontal fibres which are present in the dental cement and in the alveolar bone hold the tooth in the alveolar bone. The main characteristics of periodontitis comprise inflammation of the gum, loss of stability, formation of pockets in the dental periosteum and degradation of the alveolar bone.
The main cause of periodontitis is plaque. This consists of certain components of the saliva, food residues and bacteria and degradation products thereof. This specific form of infectious disease is in most cases caused by Porphyromonas gingivalis, Bacteroides forsythus and Actinobacillus actinomycetemcomitans. The continuous release of bacterial toxins, in particular lipopolysaccharide (LPS), leads to a non-specific immune defence reaction. LPS-stimulated macrophages release prostaglandin E2 (PGE2) and pro-inflammatory mediators, such as for example interleukins (e.g. IL-1 beta) and TNF-alpha, in the affected tissue of the patient. The pro-inflammatory mediators trigger the release of further PGE2s and matrix-destroying metalloproteinases (matrix metalloproteinases, MMPs) from the invasive fibroblasts, which destroy the extracellular matrix of the surrounding connective tissue. This in turn allows bacteria which are actually in contact with the exposed gum to penetrate deeper into the underlying connective tissue and there to drive the inflammatory process further, so that eventually the junction between the top layer of the epithelium and the root is lost. As a result a pocket in the gum is formed. The body's reaction to this is an inflammation of the gum and the dental periosteum with damage to the alveolar bone. In the final stage of periodontitis, the person affected is at risk of tooth loss.
However, in addition to bacteria, chemical or mechanical damage can also cause irritation or inflammatory reactions of the gum or the oral mucosa. Pro-inflammatory mediators, in particular interleukins such as IL-1 alpha and PGE2, are released in this process (Reilly, D. M. and M. R. Green (1999)).
Irritation and infections of the airways affect the respiratory tract (of people or animals). The respiratory tract is subdivided into three sections: (i) the upper airways, incl. nose and paranasal sinuses and pharynx, (ii) the lower airways with larynx and trachea and (iii) the lungs with bronchi, bronchioles, pulmonary alveoli, etc.
“Irritation and infections of the upper airways” designate in particular an acute infection, which affects the upper airways, nose, sinus, pharynx and/or larynx. In the United States of America, ca. one billion acute diseases of the upper airways are recorded each year. Irritation and infections of the upper airways include rhinosinusitis (common cold), sinusitis, pharyngitis/tonsillitis, laryngitis and sometimes bronchitis. The symptoms of these infections often include swelling of the nasal mucosae, cough, nasal catarrh, sore throat, fever, sneezing and pressure sensation. The symptoms as a rule start 1 to 3 days after contact with pathogenic germs, mostly viruses. The symptoms typically cease in 7 to 10 days, but can also persist for longer.
A commonly occurring (airway) infection is pharyngitis. Pharyngitis is in most cases a painful inflammation of the pharynx and is thus commonly also described as sore throat. Inflammation of the tonsils, tonsil inflammation or tonsillitis can arise at the same time.
For infections of the upper airways there are essentially three therapeutic approaches: symptomatic, remedial and preventive. Symptomatic therapy aims to alleviate symptoms and pain. Remedial therapies are intended to treat the pharyngitis by preventing its spreading and accelerate the healing process. Preventive therapy is intended to prevent the outbreak of an infection.
Remedial therapies are most effective against bacterial infections, e.g. streptococci. Many preventive therapies are also remedial.
With viral infections, the recovery from a pharyngeal inflammation as a rule occurs spontaneously within a few days. Hence the favourite method is symptomatic therapy.
Various non-antibiotic therapies for throat inflammation have been tested in controlled studies. Analgesic therapies are among the most effective here.
The symptomatic therapies for infections of the upper airways include: formulations whose purpose is to act remedially or symptomatically and which can present in the following forms:
solid galenical forms (such as for example tablets (with and without coating, with and without modified release), sugar-coated tablets (with and without coating, with and without modified release), capsules (soft or hard gelatine capsules with and without modified release), granules (with and without modified release), powders (with and without modified release), suppositories (with and without coating, with and without modified release), lozenges and chewing gums),
liquid forms (such as for example solutions, suspensions, emulsions, syrups (colloquially cough syrup), mouthwashes, gargle solutions, throat sprays or nasal sprays, nasal drops, nasal rinse solutions, nasal powders, nasal ointments or ear drops, ear sprays, ear rinse solutions, ear powders and aural tampons),
semisolid forms (such as for example hydrophobic ointments including for example: hydrocarbon gels, lipogels, silicone gels, oleogels and water-absorbing ointments including for example absorption bases, hydrophilic ointments, hydrophilic gels (hydrogels) or pastes,
Inhalants (such as for example compressed gas dispenser inhalers, powder inhalers, inhalers with atomisers, and inhalation concentrates for inhalation), and
active substance-containing plasters or other therapeutic systems.
The gastrointestinal tract (also called digestive tract) is the system of internal organs which take up and digest the food, in order to absorb nutrient substances therefrom, to obtain energy and to excrete the food components remaining. Accordingly, the main functions of the digestive tract are food uptake, digestion, absorption and excretion.
The upper digestive tract consists of the mouth, pharynx, oesophagus and stomach. The mouth contains the oral mucosae, which contain the openings of the saliva glands, the tongue and the teeth. Behind the mouth lies the pharynx, which leads to a hollow muscular tube, the oesophagus, which in turn leads into the stomach. The small intestine is joined to the stomach. The lower digestive tract consists of the intestines and the anus.
The intestines consist of the intestine, the small intestine, which consists of three parts, duodenum, jejunum and ileum, the large intestine, which also consists of three sections, caecum with vermiform appendix (blind gut), the colon (rising colon, transverse colon and descending colon) and the rectum.
The commonest inflammatory conditions of the digestive tracts include gastro-oesophageal reflux diseases, heartburn and gastric ulcers. The therapy usually includes firstly reduction of the symptoms and reduction of the inflammation in the tissue and secondly longer-term therapies in order to prevent reappearance of the symptoms.
Other inflammatory diseases of the digestive system, inter alia, are milder inflammatory diseases such as irritable bowel syndrome (IBS) and inflammatory diseases of unknown aetiology and chronic inflammatory intestinal diseases (IBD), such as for example chronic colitis (ulcerative colitis).
There is a particularly great need for suitable applications for the prevention or treatment of chronic inflammatory intestinal diseases, in particular chronic colitis (ulcerative colitis).
Chronic inflammation can appear as a cause of various diseases and living conditions. It can be associated with the most diverse conditions such as arthritis, some types of cancer, colitis, diabetes mellitus, coronary heart disease, obesity, Alzheimer's disease and immune dysfunction.
There are essentially two enzymatic pathways for regulating inflammation. The lipoxygenase pathway (5-LOX) results in the production of leukotrienes, which have a pro-inflammatory action. The second pathway is the cyclooxygenase pathway (COX-1 and COX-2). A high level of COX-2 indicates inflammation. Further inflammation markers are tumour necrosis factor (TNF-α), nuclear factor κB (NF-κB), interleukin-6 (IL-6), interleukin-17 (IL-17) and interleukin-1-β (IL1-β). The enzymes, cytokines and metabolites thereof increase the production of prostaglandins and leukotrienes, which function as intercellular mediators, and are connected with the inflammatory process. Regulation of the enzymes LOX-5 and COX-2 in particular can have a positive effect in the development/suppression of inflammation.
A diet which is based on much sugar and starch, and fat and trans fatty acids, has a direct connection with chronic inflammation. Oxidation of multiply unsaturated fats and fatty acids in vitro and in vivo leads to the formation of reactive oxygen species (radicals), and to the formation of nitrogen oxides. These compounds can initiate and/or promote the first phase of an inflammatory process. Damage to the DNA can result from this.
Over its whole length, particularly in the region of the intestine, the gastrointestinal tract is susceptible to inflammation, hence it is very important to inhibit corresponding processes and to prevent inflammation. Without treatment, harmful processes can lead to irritation, acute and chronic inflammation, and onwards to cancer.
Chronic inflammatory diseases of the digestive tract mucosa represent a considerable health political problem. Younger people in particular are falling ill, whose whole lifestyle is severely affected thereby, and who have to rely on medical care throughout their life. The aetiology/pathogenesis of the chronic inflammatory diseases of the digestive tract is not completely clear. However, it is believed to be a cause of the onset of a disorder of the intestinal barrier.
Ulcerative colitis and Crohn's disease are inflammations of the intestine, which exhibit characteristic accompanying symptoms such as diarrhoea, blood in stools, abdominal pains and cramps, and weight loss. At the same time, the intestinal mucosa appears red and swollen and often bleeds on the slightest touch.
The epithelial cells of the mucosa represent the cell layer closest to the surface. The intestinal epithelial cells constitute the greatest contact area of the body with the outside world. They absorb food and at the same time prevent the penetration of pathogenic organisms. The latter is promoted by chronic physiological inflammation. This is subject to a range of control and regulatory mechanisms in order to avoid on one hand the penetration of pathogenic germs and on the other hand damage due to the inflammatory mediators themselves. For this, the epithelial cells interact with the cells of the mucosa-associated immune system.
Intestinal epithelial cells possibly have an important role in the pathogenesis of chronic inflammatory intestinal diseases. The main model for the onset of chronic inflammatory intestinal diseases describes the following scenario: a defect in the structural integrity of the intestinal epithelium leads to an invasion of antigens from the intestinal lumen. In genetically predisposed patients, this process can trigger a chronic inflammation through activation of the mucosa-associated lymphatic tissue. A disorder of the cell-cell contact due to genetic modification of the N-adherin or keratin 8 triggers a chronic intestinal inflammation. Epithelial cells possess a large number of receptors for signal uptake. These in particular include receptors for the recognition of bacterial motifs, so-called pattern recognition receptors.
One such recognition receptor for bacterial motifs is the so-called NOD2/CARD15 protein. NOD2/CARD15 is a member of the NBS-LRR protein family (for nucleotide-binding site and leucine-rich repeat), the members whereof all play a part in the intracellular recognition of microbes and components thereof and which also include for example Apaf-1 and CARD4/NOD1, which possibly also can play a part in certain patients. When bacterial components bind to NOD2/CARD15, this normally leads to activation of the pro-inflammatory transcription factor NF-κB.
Adherent E. coli strains have been found in ulcerations in patients with Crohn's disease. In general, in patients with IBD or IBS, considerably more bacteria are directly adjacent to the intestinal epithelial cells than in the normal mucosa, which is protected from contact with bacteria by a mucus layer. This observation supports the hypothesis of the importance of bacterial translocation in the pathogenesis of IBD.
The currently available therapies for the treatment of Crohn's disease and ulcerative colitis can alleviate, but not cure, the disease symptoms. Most therapies end with a resistance to the antibiotic and surgical intervention.
JP 2007/077122 describes the use of plant proanthocyanidins, for example from apple, pear, apricot, grape, guava, hops, barley or adzuki bean for the prevention of intestinal inflammation, especially in the case of ulcerative colitis. The recommended daily intake is 100 to 2500 mg apple extract or corresponding quantities of apple proanthocyanidins. The effect of the apple proanthocyanidins was confirmed in mice with acute ulcerative colitis caused by dextran sulphate (DSS, 2.5%) over a period of 20 days.
Models of the DSS-induced colitis (acute or chronic) are rapid, simple to perform, well reproducible and inexpensive. They enable the real-time study of the inflammatory process from onset up to remission and are thus very suitable for studies of epithelial regeneration and wound healing and for drug screening.
The S3 Guideline “Diagnosis and Therapy of Crohn's disease” summarizes the results (on the treatment of the aforesaid diseases) of an evidence-based consensus conference of the German Society for Digestive and Metabolic Diseases with the competence field Chronic inflammatory intestinal diseases (Z Gastroenterol 2008; 46: 1094-1146). For the therapy of such diseases, inter alia budesonide, systemically active steroids, sulfasalazine, azathioprine/6-mercaptopurine, methotrexate and anti-TNF-alpha antibodies have until now been used.
Overall, however, there is still a need for suitable uses for the prophylaxis and/or treatment of inflammation.